Age-related neurologic disease is a significant and growing burden on our society. Although the largest share of research effort has typically been devoted to the common neurodegenerative illnesses (such as Alzheimer's disease, or AD), the reality is that nearly all cases of neurodegenerative disease possess elements of mixed pathology. Individuals diagnosed with AD frequently harbor neuropathologic hallmarks common in other diseases. For example, tau pathology is also found in some forms of frontotemporal dementia, ALS, and other forms of neurodegenerative disease, and is also believed to be a key form of neuropathology that develops following traumatic brain injury. Cerebrovascular disease (CVD) is abundant in individuals with a history of obesity (and type 2 diabetes, or T2D), which have a well known elevated risk of dementia. In general, it is actually quite rare to identify AD cases lacking elements of co-morbid cerebrovascular pathology. It is unclear as to whether these elements of pathology contribute to dementia in an additive or synergistic manner. In recent studies in our lab, we have observed an intriguing relationship between various aspects of neuropathology that could potentially connect to AD and CVD. We have identified a membrane ion exchanger, NHE1 (SLC9A1), as potentially involved in both pathologic processes. NHE1 has been shown to be involved with neuronal injury, and tau pathology as our preliminary data indicates. This project seeks to determine whether the function of this exchanger is important for either, or both, of these pathologies. This project combines both genetic and pharmacologic approaches to explore this exciting new target that has not previously been examined as a major player in age-related neurodegenerative disease. In specific aim 1 (SA1), we will investigate the mechanism of the membrane ion exchanger NHE1 in a unique mouse model combining AD- and CVD-related pathology, using a highly specific pharmacologic agent. In SA2, we will investigate how this membrane ion exchanger drives the formation of tau pathology, by over expressing tau on a background of NHE1 genetic reduction. Efficacy will be determined using a range of immunohistochemical, molecular, and biochemical markers of pathology, as well as gauging changes in cognitive function. We hypothesize that NHE1 will be responsible for multiple aspects of neurodegenerative disease pathology, and that interfering with its activity will ameliorate these problems, and will alleviate cognitive dysfunction. This is a highly innovative hypothesis that, to our knowledge, has not been previously explored. Another strength of this proposal is the use of a novel mouse model with unique features. This project has the capacity to significantly improve our understanding of co-morbid neuropathologies, and could have significant implications for the treatment and prevention of age-related neurodegenerative disease.